CA2067307A1

CA2067307A1 - Optimized tablet formulation

Info

Publication number: CA2067307A1
Application number: CA002067307A
Authority: CA
Inventors: Ashok V. Katdare; John C. Cunningham
Original assignee: Individual
Current assignee: Merck and Co Inc
Priority date: 1991-04-29
Filing date: 1992-04-27
Publication date: 1992-10-30
Also published as: NO933806L; WO1992019228A1; ZA923068B; CZ227093A3; JPH06157309A; CN1066184A; NZ242486A; MX9201969A; SK117793A3; EP0511767A1; KR920019340A; AU1522992A; IL101679A0; IE921384A1

Abstract

TITLE OF THE INVENTION
OPTIMIZED TABLET FORMULATION

ABSTRACT OF THE DISCLOSURE
An optimized direct compression tablet formulation comprises in parts by weight from about 10% to about 45% of 2-butyl-4-chloro-1[(2'(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)-imidazole, from about 20% to about 40% microcrystal-line cellulose, from about 10% to about 30% lactose, from about 0.5% to about 0.9% magnesium stearate, and from about 5% to about 35% pregel starch.

Description

0597~/ 605~A

TITLE OF T~E INVE.NTION
OPTIMI Z;ED TABLET FORMULATI ON

BAÇE~BOIJNP OE ~I;13 INVENTI(:)N
As is known from the prior art, e.g., published European Patent Application 0 253 310, 2-butyl-4-chloro-1[(2'(1~-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(~ydroxymethyl)imidazole, hereafter called DUP 753, inhibits the action of the hormone angiotensin II (AII) and is useful therefore in alleviating angiotensin induced hypertension. The enzyme renin actæ on a blood plasma a2-globulin, ~:~ an~iotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to 2s AII. The latter substance iæ a powerful vasopressor agent which has been implicated as a causative agent : for producing high blood pressure in various : mammalian specieæ, such a~ ~he rat, dog, and man.
: DUP 753 inhibits the action of AII at itæ receptoræ

.

.: . : . .
. . , . : :
., ~

.

~7~7 on target cells and thus prevents the increase in blood pressure produced by this hormone-receptor interaction. By administering ])UP 753 to a species of mammal with hypertension due to AII, blood pressure is reduced. DUP 753 a:Lso is useful for the treatment of congestive heart failure.
European Patent Application 0 253 310 discloses the following tablet formulation for DUP
753:
lo Ingr~dien~ O;uantity (mg) % (wt2 DUP 753 100 20.41 Colloidal SiO2 0.2 0.04 Magnesium stearate 5 1.02 Microcrystalline cellulose 275 56.12 Starch 11 2.25 Lactose 98.8 20.16 OBJEÇ~S OF THE INVENTION
It is an object of the present invention to provide an optimized direct compreæsion tablet formulation containing DUP 753 as active ingredient.
Another object is to provide an optimized submultiple formulation containing the active ingredient of the ; present invention. A further object is to provide a DUP 753 tablet formulation having æufficient mechanical strength to permit film coating. These and other objects of the present invention will be appar~nt from the following description.
S~MMARY OF THE INVENTION
An optimized direct compression tablet formulation containing DUP 753 as active ingredient comprises in parts by weight from about 20% to about .. , . - :
- ~ ~

.

.
.
, ~067~07 ., '~
40~/0 microcrystalline cellulose, from about 10% to about 30% lactose, from about 0.5% to about 0.9%
magnesium stearate, from about 5~/0 to about 35% pregel starch, and ~rom about 10% to about 45% of DUP 753.
s DETAILED DESCRIPTIOM
; In developing a new tablet dosage formulation, it is necessary to balance the often-competing needs of the clinical, marketing and production areas. In order to properly do so:

1. Each ta~let much be uniform in weig~t and contain the appropriate amount of active ingredient. The flowability of the ~ormulation i9 critical.

2. The active component of each tablet must be readily available as needed; hence the tablets must have the proper type of drug release and the appropriate dissolution characteristics.
The solubility of the drug i9 critical.

3. The tablet formulation must be physically and chemically stable. Proper choice o~ method of manufacture and selection of excipients is critical.

4. The tablets must have the mechanical integrity to withstand damage during ; 30 manufacturing, pac~aging, ~hipping and use.
~ , : .
.
~ ~ , - "
, :
, 2~7~7 0597H¦6052A - 4 - 18319 5. The chosen method of manufacture must be efficient, reproducible, and amenable to automation.

6. The tablets must be elegant in appearance and aesthetically pleasing.

The present invention relates to an optimized direct compression tablet formulation containing DUP 753 as active ingredient.
Dep~nding upon the properties of the active component, some of the objectives may assume more importance over others. For example, in the case of DUP 753, where an immediate release dosage form is reguired, the proper dissolution specification i8 not dif~icult to achieve due to the inherently high water solubility of this drug. ~owever, since the tablet will need to be iilm coated to mask its bitter taste, the tablets must have sufficient mechanical ~trength to withstand this additional, often-abrasive processing step.
Often when a new drug entity is in early development, the clinical research group will request a dosage form with a certain type o~ drug release, e.g., immediate, sustained, or controlled release, along with a particular dosage range~ although doses become well de~ined only approximately 6-9 months into a program. The rising dose study gives some early indication of what doses may be pharmacologically active and physiologically viable.
As the clinical research group conducts Phase I
studies, the proposed dosa~e range may be revised.
Conc~rrently with these Phase I studies, the .. . . .
; ~ . , ~, :. . . .;' :
,~ . :
. .

~ ~3 63 7 3 ~3 r7 ;l development of a formula is underway. Since the dosage level can dramatically affect the tablet composition, the pharmacist must develop a formula that is Plexible and amenable to any revision in the dosage level. An excellent approach is to use submultiples which is described below.
Submultiples means keeping the relative composition of the tablet unchanged and only changing the weight of the tablet to contain a desired dose.
For example, for a 20% drug composition:

dose (mg~ Ta~Wt. (mg) This approach will:
l. keep the development work to a minimum;

2. provide flexibility in changing doses without changing the compositions;

3. reduce stability, analytical, bioequivalence, bioavailability, formula characterization and administrative work significantly; and 4. require much smaller bulk supplies during formulation development compared to the ; situation when different doses have different compositions.

` :
~' .

2~67307 ,:

The submultiple approach i9 useful except when the dose ranges are uncomortably wide such as, for example, 1 mg to 400 mg. However, if they are manageably wide such as 2.5 - 80 mg, it is still possible to use this approach by using two submultiples: one for 2.5 (50 mg tablet), 5 (~00), and 10 (200 mg) and one for 20 mg (100 mg tablet), 40 : (200 mg), and 80 (400 mg). This approach still : reduces the workload significantly.
^ lo Direct compression was selected as the .~ method o~ manufacture bacause it is much more economical, much less labor-intensive and ea~ier to characteri~e than other tableting methods, and the specific pxoperties of DUP 753 show that it is suitable for direct compression:

1. DUP 753 exhibits acceptable flow properties and does not have a tendency to agglomerate or segregate due to static charge.

2. While the compactibility of DUP 7S3 ~ decreases as its % in the tablet increases, -; sufficient compactibility is obtaînable at acceptable drug loading levels.
~ 25 3. The percentage of drug in t~e tablet i8 sufficiently high that content uniformity in the ~ direct compression mixtures is not a problem.
.~
; 30 4. Uniformity o~ bulk drug and excipient properties can be controlled to produce direct compression tablets reproducibly and successfully.

"

. .- , ,. ~ , . ; ~
, ,, .
: ~ . : '. ~ '.

2 (~ ~ 7 r~ ~ 7 The percent of DUP 753 will depend in part on the drug loading profile and the dosing requirements. As a part of additional preformulation work relevant to tablet development, we evaluated the effect of % drug loading on compaction properties and in turn tablet properties such as breaking strength and friability. We evaluated drug loads o~ 0%, 10%, and 50%. The results showed that as the V/o drug load increased, the breaking stren~th decreased. The lo breaking strength values at 50% drug load were unacceptable. Si~ce DUP 753 is very bitter it requires film coating. Development of a strong tablet was set as a major objective to obtain a sufficiently hard tablet that can withstand ~ilm coating As development work progressed, it became evident that the clinically effective doses would be in the range of from about S0 mg to about 200 mg.
Since it was previously determined that 50%
drug loading results in unacceptable compactibility, 33% drug loading was chosen. The 33% drug loading gives an elega~tly acceptable size tablet over the 50 - 200 mg dose range.
50 mg = lS0 mg tablet 100 mg = 300 mg tablet 200 mg = 600 mg tablet Excipient selection depends on various factors, such a~, the choice of DUP 753 percent, the objectives of the tablet formulation development, and the method of manufacture. The ~oremost property an excipient must possess is compatibility with DUP

, , :-' : ' ' 2~73~7 ; 0597H/6052A - 8 - 18319 ,:
753. The requirement for a hard, nonfriable tablet that could withstand $ilm coati:ng, necessitated choice of other e~cipients with excellent compactibility. Microcrystalline cellulose was found to have excellent compactibility with DUP 753.
In addition, microcrystalline clellulose has a bulk density close to that of DUP 753 (0.3 - 0.4 g/ml) which may prevent segregation. Microcrystalline cellulose also acts a-s a wicking agent by virtue o~
its structure and promotes disintegratiozl. Although in this particular case disintegration/dissolution is not a main concern since the drug is highly soluble, microcrystalline cellulose has been found to promote good adherence of film coat and formation of a sufficiently hard, nonfriable DUP 753 tablet.
Various grades such as, ~or example, Avicel PH 101, Avicel P~ 102 and Emcocell are suitable Magnesium stearate was found to be compatible with DUP 753 and it was also selected as an excipient as it is an excellent lubricant. Its surface area and particle shape are of utmost importance in its function as a lubricant. Although magnesium stearate is generally a very small proportion of the total tablet, it ie believed to be ~5 an extremely important and essential variable. Other materials that can be substituted in whole or in part for magnesium stearate are, for example, stearic acid, calcium stearate, sodium stearyl fumarate and talc.
30 A disadvantage of microcrystalline cellulose is believed to be its susceptibility to over-lubrication by magnesium ~tearate. Overlubrication can occur due to too much magnesium stearate or too .
. .
:. ~
i .

, ~, ' ' ' ; ' .. .. i .

2~673~7 long a lubrication time. Magnesium stearate covers the surface of particles or granules during the lubrication step. This surface magnesium Stearate can dramatically reduce the ætrength of tablets by interfering with bonding between particles or granules during compaction. To prevent this overlubrication, lactose was added. Besides being compatible with DUP 753, lactose compacts by brittle fracture. Lactose particles fracture to generate new lo unadulterated surfaces that may not only promote bonding but also reduce the risk of overlubrication since magnesium stearate does not cover the new fractured surfaces. Lactose is soluble, mois~urc insensitive, erodes easily in aqueous media, and available worldwide. It was believed that the inclusion o~ lactose also will improve the bulk density of the powder mixture which in turn should improve die filling at higher speeds. By way of illustration, examplee of suitable lactoses are anhydrous lactose, fast flow lactose and spray dried lactose.
To further improve the ~ulk density reguirement, pregel starch was included. Besides having good ~low properties, it was shown to be compatible with DUP 753, posse~ses higher bulk density, is easily available worldwide and is known to have a good guality control. Pregelatinized (pregel) starches are prepared by cooking and drying starch slurries. The precookin~ process swells the starch granules and preconditions them so that they will thicken and gelatinize in cold liquids without the need for subsequent heating. By way of illustration, a ~pecific example of pregel starch is NF 1500 (StaRx).

.. . .

, ' . ' ~ ' ~

.
.

2~673~7 i Since the relative proportions of the actlve and the excipients were believed to affect the final tablet proper~ies 9 a mixture type of design naturally evolved. One type of mixture design is referred to as a slack variable design. In a slack variable design, one of the factors, called the slack or filler variable, is allowed to vary such that the ~/0 of the remaining factors ~ the % of the filler variable equals 100% of a fixed total. A slack variable design was used to optimize the DUP 753 formulation as the uppar and lower bounds on the factor ranges satisfied the requirements for a slack variable design.
Pregel starch, which serves as a disintegrant, was believed to be the least important contributor to a formulation containing such a highly soluble active as DUP 753 and, therefore, it was selected as the filler.
In addition to selecting pregel starch as the filler, it was decided to fix the relative amount of DUP 753 at 33.33%. As earlier stated, thiæ has a few important advantages: (1) compactibility problems due to high drug loading (>33.33~/0) are avoided; (2) the submultiple approach will work easily in the proposed dose range of 50-200 mg; and (3) interpretation of the re~ults should be less difficult since one very important factor, % active, is kept constan~ for all dosage formulationæ.
After selecting pregel starch as the filler ; 30 and deciding to keep the relative amount of active to 33~33%, the following rangeæ ware selected for initial evaluation:
;

,; ,.~ . ~ .
~'7 ' ~ ' :

, ', , ' : ' , , , . :, ' ' _ , ~6~7307 0597H/6052A ~ 18319 ,:

Mi crocrystal l i ne Magnesi um , ~Q~ Lactose ~ ~h DUP 753 LDW 20% 10% 0.3C/, Filler to 33.33%
Hi~h 35% 30% l.Z% 100% 33.33%

When compositions within the foregoing ranges were tested for feasibility, the two worst formulations o were identified:

1. 20% microcrystalline cellulose, 30%
lactosc, 0.3% magnesium stearate, 16.37% starch, and 33.33% DUP 753; due to binding caused by underlubrication.

20% microcrystalline cellulose, 10% lactose, 1.2% magnesium stearate, 35.47% starch, 33.33%
DUP 753; due to poor compactibility caused by : ~ overlubrication.

Both formulations proved to be non~easible. This finding necessitated constricting the range of '~ magnesium stearate. Therefore, ~tudies were 2S conducted wherein the range of this ingredient ranged from a low of about 0.5% to a high of about O.g%.
The formulation found to have the hi~hest tensile strength/applied force (TS/AF) ratio was composed of 35% microcrystalline cellulose, 17.5%
30 lactose, 0.8% magnesium stearate, 13.37% starch and 33.33% DUP 753. To minimize the potential for over-lubrication, further experiments were conducted having a narrower range of magnesium stearate. These ~:-, . . . .
--~ . , ~ - .

:.

.

~7~

studies resulted in a formulation composed of 35%
microcrystalline cellulose, 17.0% lactose, 0.7%
magnesium stearate, 13 . 97~/o starc:h and 33.33% DUP 753.
The ~ollowing examples illustrate the present invention without, however, limiting the same thereto. While specific techniques are described therein for preparing direct compression tablets it is to be understood that other techniques may be employed as well.

EXAMPL~ 1 A direct compression composition according to the present invention is prepared in a 250 g batch from the ~ollowing ingredients.

% Gram$
Microcrystalline cellulose (Avicel P~ 10~) 35.0 87.5 Lactose 17.5 43.75 20 Magnesium stearate 0.8 2.0 Pregel starch NF 1500 (StaRx) 13.37 33.42 ~UP 753 33.33 83.33 The foregoing formulation was prepared for tablet manufacture by the following process. The microcrystalline cellulose, DUP 753, lactose and pregel starch were added to a V-blender having a size of approximately 1 liter, mixed for 5 minutes at a rotational speed of 24 rpm, and screened through a 30-mesh (US) screen. The mixed powder was re-mixed for an additional 5 minutes at the same rotational speed of 24 rpm and then spread onto tray paper. The magnesium stearate was manually forced through a ...
- . . ..
... .
, . .

: :
, ' ~' ~ 73~7 60-mesh ~US) screen on top of the powder on the paper. The magnesium stearate then was worked gently into the mixed powder, and the resulting mixture blended in the V-blender for 4 minutes at 24 rpm.
The blended powder wa~ stored in a polyethylene bag until compaction.
Tablets with a final weight of 100 mg were compacted on the instrume~ted St:okes F press using flat, round, 0l.25 inch (0.64 cm) tooling. The tablets had a TS/AF ratio of 257.1 kPa/~N, and were eminently suited for film coating.

E~ E_~
A direct compression composition according to the present invention is prepared in a 250 g batch from the following ingredient~.

/ Gr~a__ Microcrystalline cellulose ~Avicel PH 102) 35.0 87.5 Lactose 17.0 42.5 Magnesium ~tearate 0.7 1.75 Pregel ~tarch NF 1500 (Sta~ 3 97 34.92 DUP 753 83.33 The foregoing formulation was prepared following the procedure of example 1.
~XAMPLES 3-12 The following Table shows various additional acceptable formulations of the pr~sent invention wherein aIl ingredient~ are varied in quanti~y except DUP 753 which i3 maintained at 33.3%.

., : . . . ~ .
- ~ :
, , , . . . .

206~3~7 .

~ U
U ~ o ~
.,~ '`I o oo ~ ~ o o ~ ~ ~o Cl~ U~
U . P.
oo _l _ ~ Q~
~5~`J E r l ~ ~ ~ U~
U :J O OC~ 7 0 r ~ D V h 1~: ~ ~ ~ 1~0 X OD C~
~ ~ O
,~ ~ ~
, ~ r~
r/ ~ I~ r~ d~ O U~
~ t~
.~ 10 n ~o o o o o o o o o o ~ El .~ ~ ~o P
o C~l o U~ ~ o . ,,~ X ~ ~o In , :3 ~ ,, _, o ,~ o o _~ o o o ~1 In b~
_ .,~
~' ~ ~ U~ ~ U~ ~ U~ oo o~ e~
!~ ~ ~ o~ o ~ o ~ _~ ~1 r ~ C~ ~ C`l ~ ~ C~ ~
4~ v o ~ ~rl _I ~ rl 2 0 .r u ~ ~ u; ~ ~
..cl c:
~ J ~ 3 :
_ -1 ~O _I OD _I CO ~1 OD 11~ U) r I ~ ~ O 1~
, ~
_I v ~:
o o o o o o o o u~ ur, ~7,1 ,~
ur~ oo ur~
, _ ; ~ o o o o o o o o o o li ~ ~
a ~ ~ ~
., ~I O O O ~ O C:~ O O O O r~ ~
; c _ O O O O ~ O O O O O ~ ~ .r ~ _ O O O O O O O O O O ~1~.) I ~
3 ~ r ~ r~ O ~ ~ ~ O

, , o o o ~ o o o o o o ~ ~ _ O ~ ~ o c: o o o o o o u~
P ~ O o o o 11~
O r~l r~l r I

:.

- ~

.

;~ , ' :, .
,. , , .
-, , , . .

Claims

1. A formulation suitable for forming a direct compression tablet comprising in parts by weight from about 20% to about 40% microcrystalline cellulose, from about 10% to about 30% lactose, from about 0.5% to about 0.9% stearic acid, magnesium or calcium stearate, sodium etearyl fumarate or talc from about 5% to about 35% pregel starch, and from about 10% to about 45% 2-butyl-4-chloro-1-[(2'(1H-tetrazol-5-yl)biphenyl 4-yl)methyl]-5 hydroxymethyl)-imidazole.

2. A tablet formed from a formulation according to claim 1.

3. A formulation according to claim 1 wherein the amount of 2-butyl-4-chloro-1-[(2'(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)-imidazole is about 33.33%.

4. A tablet formed from a formulation according to claim 3.

5. A formulation according to claim 3 containing about 35% microcrystalline cellulose, from about 17% to about 17.5% lactose, from about 0.7% to about 0.8% magnesium stearate from about 13.37 to about 13.97 pregel starch, and about 33.33%
2-butyl-4-chloro-1-[(2'(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]-5-hydroxymethyl)imidazole.

6. A tablet formed from a formulation according to claim 5.

7. A composition according to claim 5 containing about 35% microcrystalline cellulose, about 17.5% lactose, about 0.8% magnesium stearate, about 13.37% pregel starch and about 33.33% 2-butyl-4-chloro-1-[(2'(1H- tetrazol- 5-yl)biphenyl-4-yl)-methyl]-5-hydroxymethyl)imidazole.

8. A tablet formed from a formulation according to claim 7.

9. A composition according to claim 5 containing about 35% microcrystaline cellulose, about 17% lactose, about 0.7% magnesium stearate, about 13.97% pregel starch and about 33.33% 2-butyl-4-chloro-1-[(2'(1H- tetrazol- 5-yl)biphenyl- 4-yl)-methyl]-5-hydroxymethyl)imidazole.

10. A tablet formed from a formulation according to claim 9.